Phase I Trials: We have developed an integrated research program to efficiently and comprehensively identify, evaluate, and develop pharmacotherapeutic treatments for methamphetamine abuse and dependence. A key component of this program is a Phase I human clinical laboratory capable of performing interaction studies needed for assessment of safety and potential efficacy for medications under consideration for study in subsequent Phase II trials. We propose to further develop this research capacity in order to focus on medications or combinations of medications with novel mechanisms of action for the treatment of stimulant abuse and dependence, focusing on methamphetamine. The series of Phase I studies proposed in this project application as a component of the P50 Center continuation will address the following Specific Aims: Aim 1: To determine how treatment with an active medication, compared to placebo, alters cardiovascular effects produced by methamphetamine; Aim 2: To determine how treatment with an active medication, compared to placebo, alters subjective and reinforcing effects produced by methamphetamine; Aim 3: To determine how treatment with an active medication, compared to placebo, alters craving and drug-seeking behavior produced by methamphetamine. A total of four double-blind placebo-controlled studies over five years are planned. Medications to be studied include the cholinesterase inhibitor rivastigmine and the dopamine partial agonist aripiprazole combined with the GABA B agonist baclofen. Two additional studies will be designed based on the outcome of the first two studies and based on scientific developments emerging in the interim to provide safety and preliminary efficacy data for a 3rd phase II trial. A procedure is described for considering evaluation of perindopril and agents acting at the GABA transporter, (tiagabine), that are being studied elsewhere currently for cocaine dependence or other dopamine partial agonists, glutamatergic agents, or compounds from new classes that may be available.